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    Allosteric Regulation of Soluble Guanylyl Cyclase: The Nitric Oxide Receptor

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    Author
    Wales, Jessica
    Issue Date
    2018
    Keywords
    nitric oxide
    soluble guanylyl cyclase
    stimulator
    Advisor
    Montfort, William R.
    
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    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Nitric oxide (NO) signaling regulates numerous physiological processes, including vascular tone, memory formation, wound healing, sexual arousal, digestion, and renal filtration. Soluble guanylyl/guanylate cyclase (sGC) is the primary NO receptor, and functions by synthesizing cyclic guanosine-3',5'-monophosphate (cGMP) in response to sub-nanomolar levels of NO. Impaired sGC function is implicated in nearly all forms of cardiovascular disease, and small molecule stimulators of sGC represent a promising opportunity to treat vascular dysfunction. Despite recent clinical success, pharmacological development of sGC stimulators is limited by a lack of understanding as to where these compounds bind and how they function. This work describes the localization of stimulator binding to a conserved pocket in the heme domain of sGC, as well as bacterial homologues, using photoaffinity labeling, mass spectrometry, and NMR. Introduction of two tryptophan residues to the proposed binding site (I52W/L67W) mimics the effects of stimulator compounds, providing further evidence in support of our model. Additionally, drug response was reversibly decreased by covalently linking the coiled-coil domains. In summary, this work uncovers the binding site for sGC stimulatory compounds and provides mechanistic insight into drug response. Taken together, these findings lay the foundation for the development of new and improved pharmaceuticals targeted to sGC, as well as provide crucial insights into the function and regulation of this key therapeutic target.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Biochemistry
    Degree Grantor
    University of Arizona
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